2-amino and acylamino-1-(hydrocarbylsulphonylphenyl)-1, 3-propanediols



for example, Y can be alkanoylamino, haloalkyanoyl- Chester M. Suter,AlbanmN, Y., assignor to Sterling Drug F.-IN .-Y'" N-I J a ems a qn at eawar N9 Drawing. Application October 1, 195 1, I SerialNq.149,'213

tqaims- 24507562),

Thi nvemiq rel tes t certain -am no. and. as lm n -(4 h dm a bylsi lfoylp yD-lfi-riona Q s andto intermediates therefor," n l M e p rt ularlisv nvemi r ate new cemp n shafi' il fli qtmq a where, R is ahydrocarbyl. radical having 1-7. carbon atoms, and Y is an aliphaticcarboxylic acylamino radical.- The hydrocarbyl "radical'R includes saliphatic,- cycloali phatic, ca rbocyclic aryl, and be'nzyl radicalshaying 141.1 carbon atoms and represents, for example: branched andunbranched alkyl radicals, such as methyl, eghyl, n; propyl, n-butyl,isobutyl, n-heptyl, isoamyl, etc.;alk'enyl radicals, such as allyl,methallyl, etc.; cycloalkyl radicals, such as cyclohexyl, cyclopentyl,etc.; benzyl; phenyl; and 35 ortho-, meta-, and para-tolyl radicals. Theacylamino radicals represented by Y include both saturated andunsaturated aliphatic carboxylic acylamino radicals wherein thealiphatic carboxylic acyl group can be considered as being derived froman aliphatic carboxylic acid. Thus,

amino, nitroalkanoylamino, alkylmercaptoalkanoylamino, etc. Iparticularly prefer acyglic lower aliphatic carbonylic acylaminoradicals containing 1" This preferred group of'acylradica ls inclu'de'sg r ple, acetylamino, dichlor'oace'tylarriino} *Hibro oac amino,bromoacetylamino, betaf chloropropionylainiho, d1 1 fluoroacetylarnino,alpha-chloroprionylamino, trichloroacetylamino, nitroacetylamino,n'gejthylmercaptoiacgtylamino, methylsulfonylacetylamino,"ethylrnercaptoacetylamino, bu'tyrylamino, alpha-methylpPopionylamino,alpha,alpha dichloropropionylamino, iodoacetylamino,cyanoacetylariiino,methoxyacetylamino, acrylylamino,alpha-hydroxypropionylamino, etc.

The following groups of compounds embraced'by'the generic formulaherinabove are illustrative of the products provided by my invention:

2- haloalkanoylamino-l (4 alkylsulfonylphenyb- 1,3-propanediolghavingthje' formula""-" l lf QrQQ 79 i -91120 1 dHlili-fi-(heloalkyl) 2-a1kanoylamino- 1- (4- alkylsulfonylphenyh- 1,3propanediols, having the iormula 2-haloalkanoylamino 1- (4-benzylsulfonylphenyl); 1,3- Prop'ane damagingtherargmla f" 5 -2.-alkylmercaptoalkanoylamino 1.

ae re k v Z-nitioalkanoylamino-l- (4- cycloalkylsulforiylphenyl)1,3-propa ggigl, h aving the formula The 2 -aliphatic carboxylicacylamino-1-(4-hydrocarbylsulforiylplrenyl') -1;3'=i5r6paned1ols "bf inyinviitibn 'are usefulas antibiotic agentsibeing" particularlyimulate asantimicrobial agents. For eziafm l'efi they exhibit b'a'ct'ericid'a'l'and bacteribs'taticactiinf' against grafn iiegative andgram-positive bacteria and rickettsial organisms. My fieis c olnpgandsare also useful as intermediates for the preparatibn'of other valuableorganic substances. Thus, for example, they can be hydrolyzed by hotstrong mineral acids to produce the corresponding2-amino-1-(4-hydrocarbylsulfonylphenyl) -1,3 -propanediols.

The new compounds of my invention can in general be obtained byoxidizing a 2-aliphatic carboxylicacylamino-1-(4-hydrocarbyilmercaptophenyl)-1,3-propanediol by treatingit With a per-compound under acidic conditions. The reaction involved inthis nt d by the f llo ing eq ti n reference r de era" 'sub w ch"containsat least "two Ax e 3. 5.

- (4 alkylsulfo ylprocess is reppreferably employed. The reduction canbe carried out by heating the reaction mixture at 20-100 C. for severalhours or until the reaction is completed. When a lower alkanol solventis employed, generally the reaction mixture is boiled while providingfor slow distillation of the carbonyl compound, i. e. aldehyde orketone, which is formed by oxidation of the lower alkanol the compoundsof my invention include, for example, Caros acid (H2805), ammoniumpersulfate potassium persulfate, hydrogen peroxide, peracetic acid,perbenzoic acid, perphthalic acid, sodium perborate, sodiumpercarbonate, etc. Generally, it is preferable to employ as theoxidizing agent an organic peracid, such as peracetic acid or perbenzoicacid. Advantageously, ously reduced. It is generally preferred to employas the oxidation is carried out in the presence of an Organic thereducing agent aluminum isopropoxide in isopropanol solvent which isinert to the per-compound employed as or aluminum sec.-butoxide insec.-butanol. While as the oxidant. The oxidation usually proceeds mostsatlittle as one equivalent of the alkoxide can be employed isfactorilyat temperatures in the range l0l00 C., in the reduction, generally it ispreferable to employ depending on'the choice of oxidant, but for optimumabout 1.5-2.0 equivalents of the aluminum alkoxide per yields, it ispreferable, when using an organic per-acid, equivalent of thepropiophenone derivative (IV) in order not to allow the reactiontemperature to rise above about to assure optimum yields of thereduction product (ll). 65 C. The 2-aliphatic carboxylicacylamino-l-(4-hydrocar- The 2-aliphatic carboxylicacylamino-1-(4-hydrocarbylmercaptophenyl)-l,3-propanediols (II) and theforebylmercaptophenyl)-1,3-propanediols (II) employed as going processfor obtaining them are described and starting materials in theabove-described process can be claimed in the copendin'g U. S. patentapplication Ser. obtained in the following manner. An alpha-aliphaticNo; 249,206, filed October 1, 1951 by Royal A. Cutler carboxylicvacylamino 4 -hydrocarbylmercaptoacetopheand Chester M. Suter. I I i v Inone (III) is treated with formaldehyde in the presence The alpha-(aliphatic carboxylic acylamino)-4-hydroof sodium bicarbonate orequivalent alkaline condensacarbylmercaptoacetophenones (III) arereadily'obtained, tion catalyst, thereby producing an alpha-aliphaticcarfor example, by treating the appropriate alpha-amino-4- boxylicacylamino-beta-hydroxy-4rhydrocarbylmercaptohydrocarbylmercaptoacetophenones (V) in conventional propiophenone (IV);and the propiophenone derivative fashion with an aliphatic carboxylicacylating agent such thus obtained is reduced by treatment with anoxidizable I as an acyl halide or anhydride. The acylation can bealuminum lower alkoxide, thereby yielding the desired carried out, forexample, by heating the acylating agent Z-aliphatic carboxylicacylamino-l-(4-hydrocarbylmerand the amine (V) in=an anhydrous organicsolvent or.

in an alkaline aqueoussolution. The temperature of the reaction canbevaried withinrather wide limits, but a range of 0100 C. is generallysatisfactory.

HCHO

R-s-Q-o-on-o'rmnt alkaline captophenyl)-l,3-propanediol (II). Thereactions involved in this process are represented by. the followingequations ll condensation O Y catalyst i yreduction HY II The. alphaamino 4 (hydrocarbylmercapto) acetophenones (V) are themselvesconveniently prepared from hydrocarbylphenyl sulfides in accordance withthe following sequence of reactions:

In the initial, or hydroxymethylation, step of this proc.- ess,formaldehyde in the form of ,a gas, aqueous or. alcoholic solution orparaforrnaldehyde is interacted with the acylamino-ketone (III). Thisreaction is most conven- The 2 -(aliphatic carboxylicsacylamino)-1-(4-hydroiently carried out at 20-50 C., but temperaturesconcarbylsulfonylphenyl)-l,3-propanediols (I) of my invensiderably aboveand below this temperature range, for i I example in theI range CI also.afiord ti f t tion are readily deacylated oy treatment with hot mineralIBSUHSI The a u of Catalyst employed is not critical, acids to yield thecorresponding free amines having the but for best results it ispreferable to employ the smallest formula amount of catalyst suflicientto bring about a reasonably rapid reaction. In general, about 0.01-0.10mole R B01 '0H O|H CH1OH of thecatalyst is sufiicient toalfordsatisfactory results. O H NH,

The latter, or reduction, step of the process can be car- VI ried out bytreating the propiophenone derivative (IV) These novel amines (VI) arereadily acylated to yield obtained by the hydroxymethylation step withan oxidizacylamino derivatives and if desired can be readily reablealuminum lower alkoxide. This reduction step is converted to thealiphatic'car-boxylic ,acylamino derivacarried out in an organic solventwhich advantageously tives (I). The amines (VI) form salts with organicand is a lower alkanol'. For purposes of convenience, a inorganic acids.

lower alkanol corresponding to the lower alkoxide is It will beappreciated that when a racemic or optically while thepropiophenonederivative" (IV) is simultane- .of the theoretical based on inactiveform of the 2-aliphatic carboxylic acylamino-l(4-hydrocarbylmercaptophenyl)-l,3-propanediol (II) is employed as thestarting matzrial in the oxidation process, there will of course beobtained a racemic form of the 2-aliphatic carboxylicacylamino-1-(4-hydroca1'bylsulfonylphenyl)-1,3-propanediol (I). On theother hand, when an optically active form of the starting material (II)is employed in the process, the product (I) will likewise be opticallyactive.- The optically active forms of the starting material (II) arereadily obtained as follows: Aracemic form of the compound (II) isdeacylated by treatment with a hot mineral acid to yield a racemic formof 2-ami-no-1-(4-hydrocarbylmercaptophenyl)-l,3-propanediol (VI'I) whichis resolved through use of an optically active organic acid. Theoptically active forms of the amines (VII) thus obtained are thentreated with an aliphatic carboxylic acylating agent to yield thedesired optically active forms of the compound (II).

My invention is illustrated by the following examples without, however,being limited thereto.

EXAMPLE 1 Z-aCetyZaminO-I (4 -methy lsulfonylphenyl )'-1,Srpr'Opa'nedial A. ALPHA-AMINO-4-METHYLMERCAPTOACETOPHE- NONEHYDROCHLORIDE 110 g. of thiophenol was added with stirring to a mixtureof 90 ml. of 35% aqueous sodium hydroxide solution and 400 ml. of waterin a 2-liter, 3 -neck flask. To the resulting mixture, there was added139 g. of methyl sulfate from a dropping funnel atnsuch a rate that thetemperature of the reaction mixture did not rise above 60 C. whileapplying external ice cooling to the reaction. vessel. The addition ofthe methyl sulfate required about five to ten minutes. After theaddition of methyl sulfate was completed, stirring of the reactionmixture was continued for about one hour, and then the mixture wascooled. The thioanisole which separated from the mixture was dissolvedin about 400 ml; of chloroform. The chloroform solution was separated,washed with 100 ml. of dilute aqueous sodium hydroxide solution; anddried over anhydrous calcium sulfate. (In other experiments, isolationof the product from the chloroform solution resulted in recovery ofthioanisole' in a yield of 90-95% the quantity of thiophenol employed.)-

The chloroform solution of thioanisole was filtered free from thecalcium sulfate directly into a 2-liter, 3-neck flask fitted with astirrer, thermometer, dropping funnel, and outlet tube (for escape ofhydrogen chloride gas) protected by a drying tube. Sufiicient anhydrouschloroform was added to .the filtrate to bring the volume up to about800 ml. and the solution was cooled by means of an ice-methanol bath.165 g. of aluminum chloride was then added rapidly to the chloroformsolution, while keeping the temperature of the solution below C. 106 g.of acetyl. chloride was added to the solution by means of a droppingfunnel while still maintaining the temperature of the reaction mixturebelow 10 C. As the addition of the acetyl chloride proceeded, a yellowsolid gradually separated from the mixture. (In some instances, it wasfound desirable to add an additional quantity of dry chloroform to thereaction mixture inorder to facilitate stirring.) When the addition ofthe acetyl chloride was completed, the cooling bath was removed and thereaction mixture was allowed to warm to C. while continuing vigorousstirring. The thick reaction mixture was then decomposed by pouring itinto a liter of ice and water containing 3 050'ml. of concenphenone,having the formula was separatedand employed directly in the subsequentstep. I (In other experiments, by evaporation of the chloroform solutionthere: wasobtained' in 96-98% yield 4-methylmercaptoacetophenone in ahigh degree of purity.) I. I I

The chloroform solution .of 4-methylrnercaptoacetophenone was placed ina 3-liter, 3-ne'ck flask fitted with a stirrer, adroppi'ng. funnel, andan outlet tube for escape of hydrogen bromide gas. The volume of thechloroform solution was broughtup to about 1600 ml. by addition ofchloroform. About 40g. of bromine was added to the solution and themixture was allowed to stand until the reaction was initiated, ashydrogen bromide. Stirringof the mixture was then begun and a furtherquantity of g. of bromine was added during a period of three to fiveminutes. The reaction mixture was then placed under reduced pressure byapplication of a water aspiratoi in order to remove the major portion ofthe hydrogen bromide. The temperature of the solution, which containedalpha-bromo- 4-methylmercaptoacetophenone, having the formula graduallyfell, due to evaporation, to about 10-15 C. (A sample of thisbromoketone, isolated in another experiment, was obtained in the form ofsmall white leaflets, which melted at 65.5-66.5 from methanol.)

To the cold chloroform solution ofalpha-bromomethylmercaptoacetophenone, there was added 140 g. ofhexamethylenetetramine. The temperature of the mixture rose gradually toabout 305-35 C., and a white solid separated from the mixture. Themixture was stirred for about two hours and then the solid was collectedon a filter and washed with chloroform. The product thus obtainedconsisted ofalpha-bromo-4-methylmercaptoacetophenone-hexamethylenetetramine adduct,having the formula naQCQHZ-m-(oH-QMN.

and melting at approximately 140 C. with decomposition.

The alpha-bromo-4-methylmercaptoacetophenone-hexamethylenetetra'mineadduct obtained in the preceding step was placed in a 3-literflask with750 ml. of ethanol and 375 ml. of. concentrated hydrochloric acid. Asthe mixture was stirred, producing. a slurry, the solid gradu-' Thereaction product subsefrom the solution. The re-' action mixture wasthen cooled to 10 C., filtered, and the filter cake was washed with 100ml. of cold ethanol. The; damp filter cake was their slurried for'a fewminutes at 40'50 C. with 600 ml. of water containing 25 ml.ofconcentratedhydrochloric acid. After cooling the slurry to 5l0 C., thewhite solid was collected on a filter, washed with 100 ml. of watercontaining- 5v ml. of concentrated hydrochloric acid, and dried. Therewas thus obtained -141 g. of alpha-amino-4-methylmercaptoacetophenonehydrochloride, having the formula ally went into solution. quently beganto separate A: sample 'of this product when recrystallized from waterevidenced by evolution of- C., after recrystallization formed largewhite leaflets which melted at 2345-.

235 C. (dec.).

B. ALPHA-ACETYLAMINO-i-METHYLMERCAPTOACETO- PHENONE A slurry of 11 g. ofalpha-amino-4-methylmercaptoacetophenone hydrochloride in 50 ml. ofwater containing 100 g. of ice was stirred vigorously and to the slurrythere were added in one portion ml. of acetic anhydride followed by asolution of 14.5 g. of sodium acetate trihydrate in 60 ml. of water. Thetemperature of the reaction mixture, which did not rise'during additionof the acetic anhydride and sodium acetate, was allowed to warm to roomtemperature (about 25 C.) and stirring was continued for an additionaltwo hours. Sufficient concentrated hydrochloric acid was then added tomake the reaction mixture acid to Congo red paper (to dissolve anyunrecated aminoketone), and the white solid in the mixture was thencollected on 'a filter. This solid was washed with 30 ml. of water anddried. There was thus obtained 10 g. ofalpha-acetylamino-4-methylmercaptoacetophenone, having the formula whichmelted at l33.2-134.6 C. after recrystallization from acetone in theform of broad white needles.

C. ALPHA-ACF/IYLAMINOBETA-HYDROXYA-METHYL- MERCAPTOPROPIOPHENONE Amixture of g. of alpha-acetylamino-4-methylmercaptoacetophenone, 70 ml.of ethanol, 25 ml. of water, 10 ml. of formalin (37% aqueous solution offormaldehyde), and a solution of 0.3 g. of sodium bicarbonate in 10 ml.of water was stirred at 35 C. for two hours. The original thick slurrygradually thinned out and after about ten minutes the reaction mixturewas a pale yellow solution. At the end of the two-hour period, thesolution was refrigerated for about ten hours. The crystalline solidwhich separated from the cooled solution was collected on a filter andwashed with ml. of water. There was thus obtained 10.5 g. ofalpha-acetylamino-beta-hydroxy- 4-methylmercaptopropiophenone, havingthe formula This product was purified by recrystallization from ethylacetate to yield white fluffy needles which melted at 125.6-l27.8C.

D. 2-ACETYLAMINO-1- (4-METHYLMERCAPTOPHENYL)- 1,3-PROPANEDIOL A mixtureof 5 g. of alpha-acetylamino-beta-hydroxy-4-methylmercaptopropiophenone, 20 g. of aluminum isopropoxide, and 120 ml.of isopropanol was slowly distilled through a fifteen-inch column untilthe distillate gave no test for acetone. This distillation requiredabout seven hours. The excess isopropanol was then distilled from thereaction mixture and the residue was heated for thirty minutes with asolution of 10 g. of sodium chloride in 100 ml. of water. The resultingsuspension was filtered while hot and the aluminum hydroxide residuethus collected was washed several times with ether. From the filtratethere separated a white solid in the form of tiny leaflets. This solidwas collected on a filter and washed with 15 ml. of ether. There wasthus obtained 1.5 g. of 2-acetylamino-1-(4 methylmercaptophenyl) 1,3propanediol, having the formula oHQ-S-GoH-oH-CHIOH which melted at167-168 C. Recrystallization from water and then nitroethane raised themelting point to E. 2-ACETYLAMINO-1- ('4-METHYL SULFONYLPHENYL)1,3-PROPANEDIOL 1.95 g. of a '2 acetylamino 1 (4methylmercaptophenyl)-l,3 propanediol was slurried in 20 ml. of acetoneand to the slurry was added dropwise 4.5 ml. of 40% peracetic acid. (Theterm 40% peracetic acid is employed in this and the succeeding examplesto designate a commercial preparation of peracetic acid consisting of anaqueous solution containing approximately 40% peracetic acid, 5% ofhydrogen peroxide, 39% of acetic acid, and 1% of sulfuric acid, thepercentages being by weight). The temperature of the reaction mixturewas maintained at 46 C. or below by ice-cooling of the reaction vessel.After the addition of the peracetic acid was completed, stirring of thereaction mixture was continued for two hours, after which time themixture was cooled to 5 C. The white solid which separated was collectedon a filter and washed with two 5 ml. portions of cold acetone. Thisproduct was recrystallized from nitroethane to yield 1.02 g. of2-acetylamino-1-(4-methylsulfonylphenyl)-l,3-propanediol in the form ofWhite leaflets which melted at l72.7-173.7 C.

EXAMPLE 2 CH5-S m-Q-gzr-on-amon O A. 2-AMINO-1- (4-METHYLMERCAPTOPHENYL)-1,3-PRO- PANEDIOL A mixture of I 50 parts by weight of racemicZ-acetylamino-l-(4 methylmercaptophenyl)-1,3-propanediol obtained asdescribed above in Example 1, parts by weight of concentratedhydrochloric acid, and 500 parts by weight of water was warmed on asteam bath for thirty minutes. The resulting solution was cooled toabout 40 C. and was then made strongly alkaline by addition of 35%aqueous sodium hydroxide solution. The alkaline solution was thenrefrigerated. The white solid which separated from the cooled solutionwas collected on a filter. There was thus obtained 27 parts by weight of2-amino-1-(4-methylmercaptophenyl) 1,3 propanediol, having the formula HNH: This product melted at 130.7-131.9 C. after recrystallization frommethanol.

A solution of 17.5 g. of the2-amino-1-(4-methylmercaptophenyl)-l,3-propanediol described above,which of course was a racemic or optically inactive form of thecompound, in 100 ml. of methanol and a solution of 13 g. of d-tartaricacid in 100 ml. of methanol were mixed and the mixture was allowed tostand at l520 C. for about six hours. The solid which had separated fromthe solution during this period was then collected on a filter, themethanolic filtrate being retained for treatment as described below.There was thus obtained 18 g. of solid which melted at 190-196" C. Thissolid Was suspended in ml. of water and sufiicient dilute hydrochloricacid was added to effect solution of the solid. To the solution thusobtained there was added 50 ml. of 35% aqueous sodium hydroxide solutionwhich caused the separation of 11.7 g. of yellowish solid from solution.This solid melted at l27135 C. Two recrystallizations of this productfrom methanol yielded 1.5 g. of coarse white needles which melted atl52153 C. This product was a -levo-rotary form ofZ-amino-l-(4-methylmercaptophenyl)-l,3-propanediol having [a] 2 =2l (1%solution in 95% ethanol).

The methanolic filtrate retained above was distilled on the steam bathto remove the obtained was dissolved in 50 ingisolution Was treated withtion. This caused the separation of 3.0 g. of white solid which meltedat 141-150 C. This product was recrystal-- lized twice from methanol,thus yielding 1.0 g. of white crystals consisting of a dextro-rotar'yform of 2-amino-1- (4-methylmercaptoph'enyl')-1,3 propanediol whichmelted at 1'5215 3 C. and had [a] =+21 (1% solution in 951% ethanol).

The racemic amine was also resolved in the following2-amino-1-(4-methylmercapof d-N-benzoyh: thr'eonine (M. P. l49-15 1 C.;obtained by benzoylation manner: 33.0 g. of racemic tophenyl)1,3-propanediol and 34.6 g.

of d-threonine) were dissolved in 500ml. of methanol by warming.Crystallization was initiated by cooling the solution to 25 C. andscratching the inner walls of the container. The solution wasrefrigerated at 5 *C. for about ten hours and then the crystals whichhad separated from solution were collected on a filter, the filtrate (A)being retained for recovery of the dextro-rotary amine as describedbelow. The solid on the filter was washed with a few ml. of coldmethanol and dried at 70 C. There was thus obtained 313.3 g. oflevo-rotary-Z- amino-l-(4-methylmercaptophenyl) 1,3 propanediol d-N-benzoylthreonine salt which melted at 184-186" C. This crop of saltwas dissolved in 100 ml. of water containing 6.2 m1. of concentratedhydrochloric acid and the solution was then made alkaline by addition of13 ml. of 35% aqueous sodium hydroxide solution. 20 g. of sodiumchloride was dissolved in this solution which was then cooled to 5 fromthe solution and this solid was collected on a filter, Washed with alittle saturated aqueous sodium chloride solution and dried at 70 C;There was thus obtained 15.0 g. of crude levo-rotar'y2-amino-1-(4-methylmerc aptophenyl)-1,3-propanediol which melted at147-150 C. This product was recrystallized from 150 ml. of methanol toyield 11.9 g. of the pure levo-rotary amine which melted at 15I153 C. Byconcentrating the mother li'quor, 3.0 g. of solid consisting largely ofthe racemic amine Was recovered.

The filtrate (A) retained as indicated above was evaporated at reducedpressure. The residue thus obtained was dissolved in 100 ml. of watercontaining 62 m1. of concentrated hydrochloric acid and the solution wasmade alkaline by addition of 13 hydroxide solution. g. of sodiumchloride was dissolved: in this solution which was then cooled to 5 C.The heavy crop of crystalline solid which separated from the solutionwas collected on a filter, washed with a few ml. of saturated aqueoussodium chloride solution and dried at 70 C. There was thus obtained 13.5g. of crude dextro-rotary 2-am'ino-1-(4-methy1mercaptophenyl') -1.,3-

propanediol. This product wasrecrystallized from methanol to yield 8.5g. of the pure dextro-rotary amine which melted at 151-153 liquor, 5.0g. of solid amine was recovered.

consisting largely of the racemic B. Z-DICHLOLROACETYLAM-I'NO-l-(l-METHYLMERCAPTO 'PHENYL) -1,3-PROPANEDIOL A mixture of 1.1 g. oflevo-rotary Z-amino-l-(4-methylmercaptophenyl)-1,3-propanediol, obtainedas described above in part A, and 1.6 ml. of ethyl dichloroacetate washeated on a steam bath for three hours. The resulting viscous yellow oilwas dissolved in ml. of ethylene chloride and filtered hot withcharcoal, and the filtrate was allowed to cool to about 25 C. From thefiltrate-there separated 0.92 g. of tiny white leaflets. which werecollected on a filter. Recrystallization of this product, which .was adextro-rotary form of Z-dichloroacetylamino- C. A heavy crop' ofcrystals separated-1 ml. of aqueous sodium.

C. By concentrating the mother ens- FQZH-eH omQrr "H tripe-ouch fromnitroethane yielded the pure product, which melted at 111.6-1 12.6 C.and had [ct] 5=+12 (1% solution in ethanol).

In similar fashion, the dextro-rotary 2-amino-1-(4-methylmercaptophenyl) 1,3-propanediol was acylated with ethyldichloroacetate to yield a levo-rotary form of2-dichloroacetylamino-1-(4-methylmercaptophenyl) 1,3- propanediol, whichmelted at 111.6'112.6 C. and had [a] =l2 (1% solution in 95% ethanol).

Also in analogous fashion, the dichloroacetylation of the racemic amineyielded a. racemicZ-dichloroacetylamino-l-(4-methylmercaptophenyl)-l,3-propanediol, M. P.I01.2 102.4 C.

C. 2-DICHLOROACETYLAMINO-11 (l-METHYLSULFONYL- v PHENYL)-l,3-PROPANEDIOL7 g. of the levo-rotary Z-dichloroacetylamino-l-(4-methylmercaptophenyl)-l,3-propanediol obtained as described in partAabove was dissolved in 30 ml. of acetone. To this solution there wasadded dropwise with stirring 10 ml. of 40% peracetic acid. Thetemperature during the reaction was maintained at 3"945 C. by coolingthe reactionvessel. After stirring the mixture for two hours,

night at 70 C. There was thus obtained 6.2 g. of a levo-rotary2-dichlo1-oacetylan1ino-1-(4-methylsulfonyln N -cam.

A. z-nriahoMo oErrLaM'rNo-i- 4METHYLMERCAPTO- PHENYL'l-lB-PROPANEDIOL'By refluxing the racemieZ-amino-1-(4-methylmercaptophenyl)-1,3-propanediol described above inpart A of Example 2 with methyl dibromoacetate for about one hour usinganhydrous ethanol as a reaction solvent, there is produced a racemic2-dibromoacetylamino1-( 4-methylmercaptophenyl)-1,3-propanediol, havingthe formula In analogous fashion, the dibromoacetylation of thelevorotary' 2-amino- 1 -(,4-methylmercaptophenyl) -1,3-propanedioldescribed in Example 2A yields a deXtro-rotary form of the2-dibromoacetylamino-1-(4-methylmercaptophenyl)-1 ,3-propanediol, andthe enantiomeric dextrorotary amino-diol yields a levo-rotary2-dibr0moacetylamino-1-(4-methylrnercaptophenyl)-1,3-propanediol.

- 11 B. Z-DIBROMOACETYLAMINO-l-(4-M ETHYLSULFONYL- PHENYL)-1,3-PROPANEDIOL Oxidation of the racemic, dextro-rotary, andlevo-rotary forms of 2-dibromoacetylamino l (4-methylmercaptophenyl)-l,3-propanediol obtained as described above in part A yields,respectively, racemic, dextro-rotary, and

levo-rotary forms of 2-dibromoacetylamino-l-(4-methylsulfonylphenyl)-l,3propanediol.

EXAMPLE 4 2-dichlor0acetylamin0-1-(4rmethylsulfonylphehyl)-1,3-

propanediol.

A. ALPHA-DICHLOROACETYLAlVIINO- l-BIETHYLMER- CAPTOACETOPHENONE 217.7 g.of alpha-amino-4-methylmercaptoacetophenone hydrochloride obtained asdescribed in part A of Example 1 was mixed with 4.5 litersof anhydrousbenzene at 27 C. .166 g. of dichloroacetyl chloride was added in oneportion to the mixture, and the resulting mixture was refluxed andstirred for fifteen to eighteen hours. After this period most of thesolid had gone into solution. The reaction mixture was filtered hotthrough a preheated funnel and the filtrate was allowed to cool. Thesolid which separated from solution was collected on a filter, washedwith benzene, and dried. There was thus obtained 230 g. ofalpha-dichloroacetylamino-4- methylmercaptoacetophenone having theformula om-s-Qo-un-ax-onon Recrystallization of this product fromacetone yielded white needles which melted at 151.7-l52.9 C. B.ALPHA-DICHL0ROACETYLAMIN0-BE'1A-HYDRoXY-4- METHYLME'RCAPTOPROPIOPHENONE292.2 g. of alpha-dichloroacetylamino-4-methylmercaptoacetophenone wasslurried with 14.5 liters of ethanol at 40 C. 15 g. of sodiumbicarbonate and 150 ml. of formalin (37% aqueous solution offormaldehyde) were added to the mixture and stirring was continued whilemaintaining the temperature of the solution at 40-50" C. until all ofthe alpha-dichloroacetylamino-4- mercaptoacetophenonehad gone intosolution. This required about eight hours. The suspended sodiumbicarbonate was then removed by filtration and the volume of thefiltrate was reduced to 2-2.5 liters by evaporation of ethanol from thesolution under reduced pressure. The residual solution, which had anorange color, was refrigerated for about ten hours. The solid whichseparated from the solution was collected on a filter. There was thusobtained 232 g. of alpha-dichloroacetylamino beta hydroxy 4methylmercaptopropiophenone having the formula OH -S(\{(|JHOHaOH oNH-(i-CHGI:

0 Recrystallization of this product from ethylene chloride yielded tinywhite leaflets which melted at 1'47.7-1 48.5 C. C.Z-DICHLOFROACWIYLAMINO-I-(4METHYLMERCAPTO PHENYL) -1,3-PROPANE'DIOL322.2 g. of alph'a-dichloroacetylamino-beta-hydroxy-4-methylmercaptopropiophenone, '420 g. of aluminum \lSO- pr-opoxide, andthree liters of anhydrous isopropanol were placed in a 5 -liter flaskand the mixture was heated at such a rate that distillation of liquidthrough a inch column occurred at the rate of one drop per three tolfive seconds. Distillation was continued for sixteen to eighteen hoursafter which time a test for acetone in the distillate was negative. (Thetest for acetone was period the temperature of the carried out using a01% solution of 2,4-dinitrophenylhydrazine in accordance with theprocedure described in Organic Reactions, vol. 11, page 200.) Theisopropanol remaining in the reaction mixture was removed by evaporationat'reduced pressure. The dark red viscous residue thus obtained washeated on a steam bath for about-forty five minutes with 2.5 liters ofwater containing 200 .g. of sodium chloride. The sodium chloride wasadded to reduce the tendency of aluminum hydroxide to form a gel. Thehot suspension was filtered to remove aluminum hydroxide. The collectedaluminum hydroxide was slurried several times with ether to remove theadhering red oil and the ether extracts were combined with theifiltrate. The combined ether solutions were dried over anhydrouscalcium sulfate and the ether was removed from the dry solution bydistillation. There was thus obtained 310-320 g. of a dark red viscousoil. This oil was dissolved in 1600 ml. of ethylene dichloride, filteredwith charcoal, and the filtrate was cooled. The solid which separatedfrom the rfiltrate consisted of ll95 g. of 2-dichloroacetylamino-l-(4-methylrnercaptophenyD-l,3-propanediol, having the formulaoHwFQoHWoiPGmm-I which melted at 98100 C. This product was purified byrecrystallization from 550 ml. of nitroethane followed poxide, and '90ml. of anhydrous isopropan-ol was refluxedfor about thirty-five minuteswith provision for slow distillation of acetone and isopropanol from thesolution. The remaining solvent was tion' at reduced pressure; Theresidue thus obtained yielded 5.8 g. of2-dichloroacetylamino-l-(4-methylmercaptophenyl)-1,3-propanediol whichmelted at 101.2- l02.4 C.

D.) 2-DICHLOROACETYLAMINO-l- (l-METHYL SULFONYL- PHENYL)-l,3-PROPANEDIOL21 ml. of 40% peracetic acid was added to a stirred solution of 15.0 g.of 2-dichloroacetylamino-1-(4-methylmercaptophenyl)-1,3-propanedioldissolved in 55 ml. of acetone. External cooling of the reaction vesselwith ice was applied and the rate of addition of peracetic acid wasadjusted so that the temperature of the reaction mixture did not riseabove 40 C. The reaction mixture was then stirred one hour and wascooled to 5 C. The solid which separated from solution was collected ona filter. There was thus obtained 14.0 g. of a white solid consisting ofZ-dichloroacetylamino-l-( l-methylsulfonylphenyl)-l,3-propanediol whichmelted at *l79.4 180.6 C.

EXAMPLE 5 2 dichloroacetylamino 1 (4 ethylsulfonylphenyl)- 1,3-propanediol Y A. ALPHA'AMINO-l-ETHYLLIERCA'PTOACETOPHENO'NEHYDROCHLORIDE 337 g. of ethyl sulfate was added from a dropping funnelto a stirred solution of 200 g. of thiophenol in 800 ml. of 10% aqueoussodium hydroxide. The reaction mixture was then stirred for two hours.During this mixture gradually rose to then removed by evapora- 13 65 C.and then decreased to room temperature (about 25 C.) and the desiredreaction product, ethyl phenyl sulfide, separated from the mixture as anoil.- This oil was extracted from the mixture with 800 ml. ofchloroor-m. The chloroform solution of ethyl phenyl sulfide thusobtained was dried for several hours over anhydrous calcium sulfate. Thedry solutionwas' then placed in a '3-liter, 3-neck flask fitted with astirrer, thermometer, and drying tube. The solution was stirred andcooled to C. and 175 ml. of acetyl chloride was. added. 300 g. ofanhydrous aluminum chloride was then added portionwise While keeping thetemperature of the reaction mixture at 5-15 C. After the addition of thealuminum chloride was completed, the reaction mixture was allowed towarm to C. aridwa's poured into about 2 kg. of ice. The chloroformlayer, which contained the desired 4-ethylmercaptoacetopliehone, wasseparated from the mixture and placed in a 5-liter, 3-neck flask fittedwith a stirrer and dropping funnel. To the stirred solution there wasadded 75 g. of bromine". After the reaction was initiated, as shown bythe evolution of hydrogen bromide, an additional 225 g. of bromine waspractical. Thehydrogen bromide stirred solution, which containedalpha-bromol-ethylmercaptoacetophenone, having the formula mnewQg-cm-m(A sample of the bromoketone isolated in another experiment melted at74.475.4 C. after recrystallization from petroleum ether follow'edbyrecrystallization from methanol.) To the residue thus obtained, thereWas added 256 g. of hexamethylefiet'etramine, and the ture was stirredfor two hours. The solid yellowish alpha bromo 4ethylmercaptoa'cetophenone hexamethylenetetramine adduct having theformula This product melted at 186.5 lization from water which had withdilute hydrochloric acid.

B. AL'PHA-DICHL0ROACETYLAMINO- l-ETHYLMER- CAPTOACETOPHENONE A mixtureof 200 g. of alpha-amino-4-ethylmercaptoacetophenone hydrochlorideand4.5 liters of benzene was placed in a 12-liter, 3-neck flask fittedwith a stirrer and arefiux condenser with water trap. The benzene wasdistilled slowly until no more water collected in the water trap. 147 g.of dichloroacetyl chloride was added to the mixture in a single portionand the resulting mixture was refluxed for fifteen hours. The evolutionof hydrogen chloride had practically ceased at the end of this periodand all of the solid in the mixture had dissolved. The hot'solution wasfiltered. On cooling, there separated from the filtrate 139 g. of whitesolid which consisted of C. (dec.) after recrystalbeen made slightlyacid 1 4 alpha dichloroace'tylamino-4 ethylme'rcaptoacetophenone havingthe formula It This product melted at 127.6l28.8 C. afterrecrystallization from ethylene chloride. An additional 66 g. of theproduct was recovered by evaporation of the filtrate to a volume of 600ml., cooling, and collecting the solid which separated from solution. c.ALPHA-DrcHLoRoAcET'YLAMrNoThE'rA-HYDaoXY-4- ETHYLME RCAPTOPROPIOI-HENONE A mixtu're of 200 g. of alpha-dichloroacetylamino-4-ethylm'ercaptoacetophenone, ml. of formalin (37% aqueous solution offormaldehyde), 1600 ml. of ethanol, and 10 g. of sodium bicarbonate wasstirred at 40-50 C. for ten hours. The mixture was allowed to stand atroom, temperature for about fifteen hours and was then cooled to 10 C.The solid which separated from the cooled solution was collected on afilter, was washed with 150 ml. of ethanol, and dried. There was thusobtained 204 g. ofalpha-dichloroacetylamino-beta-hydroxy-4-ethylmercapt'opropiophenone,having the formula O NHfi-CHC12 0 which melted at ISO-152 C. Whenrecrystallized in the form of small white leaflets of ethylene chloride,the pure compound melted at 153.2 1543" C. D.2-DICHLCROA'CETYLAMINO-1-(4ETHYLMZERCAPTO- PHENYL) -l,3-PROPANEDIOL Amixture of g. of alpha-dichloroacetylamino*beta hydroXy-4ethylmercaptopropiophenone, 400 g. of aluminum isopropoxide, and 1500ml. of tilled slowly fol-fifteen hours. was removed by distillation atremoved by evaporation. There was thus obtained as a residue 128 g. ofred oil. This 'oil was taken up in 400 ml. of benzene and the hotsolution was filtered with charcoal. On cooling the filtrate 84 g. ofWhite solid separated from the solution. Recrystallization of thisproduct from 300 ml. of ethylene chloride yielded 73 g. of pure2-dichloroacetylamino-l-(4-ethylmercaptophenyl)- 1,3-propanediol, havingthe formula which melted at 92.4-93.4 C.

E. 2-DICHLOROACETYI1AMINO 1-(lwETHYLSULFONYIJ- PHENYL) -1,3-PROPAN EDIOL 22 ml. of 40% peracetic acid was added dropwise to a. stirredsolution of 18.5 g. of 2-dic'hloroacetylamino-1-(4-ethyhnercaptophenyl)-1,3-propanediol dissolved in 50 ml. of acetone.External cooling of the reaction vessel with ice was applied and therate of addition of peracetic acid was adjusted so that the temperatureof the reaction mixture did not rise above 40 C. After completion of theaddition of peracetic acid, the reaction mixture was stirred for onehour and was then cooled to -5" C.

on a filter and washed with two portions each of 20 m1. of cold acetone.There was thus obtained 17.5 g. of 2- dichloroacetylamino I (4ethylsulfonylphenyl) 4 1.3

Z-dichloroacetylamino 1 (4 n propylsulfonylphenyb- 1,3-prpanediol O A.ALPHA-AMINO-l-n-PROPYLMERCAPTOACETOPHE- NONE HYDROCHLORIDE A suspensionof 226 g. of aluminum chloride in one liter of dry chloroform was placedin a 3-liter, 3-neck flask fitted with a stirrer, drying tube, droppingfunnel, and thermometer. The suspension was stirred and cooled to C.with stirring and 145 g. of acetyl chloride was added. 235.5 g. ofn-propyl phenyl sulfide was then added dropwise at 5 C. The reactionmixture was stirred for fifteen minutes after addition of the sulfidewas completed, and was then poured into 1.5 kg. of ice containing 25 ml.of concentrated hydrochloric acid. The chloroform layer was separatedfrom the mixture and the chloroform was removed from the solution bydistillation. The residual oil was fractionally distilled, and thefraction boiling at 207 C. at 45-48 mm. of mercury was collected. Therewas thus obtained 253 g. of colorless oil which solidified uponstanding. This product, which was 4-n-propylmercaptoacetophenone, havingthe melted at 37.739.l C.

208 g. of bromine was added to a solution of 254 g. of4-n-propylmercaptoacetophenone in 2 liters of chloroform. After five orten minutes, the evolution of hydrogen bromide from the reaction mixturehad practically ceased, and the mixture was washed with 2 liters of 5%aqueous sodium bicarbonate solution containing ice. The chloro' formlayer was separated from the mixture and the chloroform was removed fromthe chloroform solution by distillation at reduced pressure. There wasthus obtained as a residue 300 g. ofalpha-bromo-4-n-propylmercaptoacetophenone having the formula in theform of an orange colored oil which was used directly in the next stepof the process. Crystallization of a sample of this product frompetroleum ether yielded a white solid which melted at approximately 43C.

95 g. of hexamethylenetetramine was added with stirring to a solution of176 g. of alpha-bromo-4-n-propylmercaptoacetophenone dissolved in 850ml. of acetonitrile. The temperature of the reaction mixture rose from28 C. to 42 C. and a pale yellow solid separated from solution. Afterstirring the mixture for two hours, the solid was collected on a filter,washed with two 150 ml. portions of acetonitrile, and with 300 ml. ofwater, and dried. There was thus obtained, as a pale yellow solid, 174g. of alpha-bromo-4-n-propylmercaptoacetophenonehexamethylenetetramineadduct having the formula which melted at approximately 135? C. withdecomposition.

92 g. ofalpha-bromo-4-n-propylmercaptoacetophenonehexamethylenetetramine adductwas mixed with a solution of 90 ml. of concentrated hydrochloric acidand 225 ml. of methanol, and the mixture was stirred and refluxed forthirty minutes. Initially, the mixture became dark red in color andafter about ten minutes ammonium chloride separated from the solution.The ammonium chloride was removed by filtration, and the filtrate wascooled to 5 C. Y The solid which separated from the cooled solution wascollected on a filter and dissolved in ml. of hot water. The aqueoussolution was cooled to 0 C. and the solid which separated from solutionwas collected on a filter. There was thus obtained 27 g. ofalphaamino-4-n-propylmercaptoacetophenone hydrochloride having theformula which melted at approximately tion.

B. ALPHA-DICHLOROACETYLAMINO-4-n-PROPYLME'R- CAPTOACETOPHENONE 27 g. ofalpha-amino-4-n-propylmercaptoacetophenone hydrochloridewas added to 500ml. of benzene and the resulting mixture was refluxed until no morewater distilled off into a water separator. 41 g. of dichloroacetylchloride was then added and the mixture was stirred and refluxed forthirty minutes. During this period all of the ketoamine dissolved. Theresulting reaction mixture was concentrated under reduced pressure, andthe residue thus obtained was refrigerated. The solid which separatedfrom the cooled solution was collected on a filter, washed with 5 ml. ofbenzene, and dried. There was thus obtained 16.5 g. ofalpha-dichloroacetylamino-4-npropylmercaptoacetophenone, having theformula which was recrystallized from benzene as a white solid whichmelted at 123 .2l23.8 C.

C. ALPHA-DICHLOROACETYLAMINO-BETA-HYDROXY-4-n-PROPYLME'RCAPTOACETOPHENONE A mixture of 13 g. ofalpha-dichloroacetylamino-4-npropylmercaptoacetophenone, 100 ml. ofethanol, and 8 ml. of formalin (37% aqueous solution of formaldehyde)containing 0.8 g. of sodium bicarbonate dissolved therein was stirred at40-43 C. for four hours. The reaction mixture was then cooled and thesolid which separated from thesolution was collected on a filter. Therewas thus obtained 12.5 g. ofalpha-dichloroacetylamino-betahydroxy-4-n-propylmercaptoacetophenone,having the formula omorriom-wQp-on-omou O NIP-(fi-CHCM C. withdecomposi- T his product was recrystallized from ethylene chloride,thereby yielding 10 g. of the pure compound which melted at 133.4136.8C.

D. 2DICHLOROACETYLAMINO-1-(4-n-PROPYLMER- CAPTOPHENYL)-1,3-PROPANEDIOL IA mixture of 9 g. ofalpha-dichloroacetylamino-betahydroxy-4-n-propylmercaptopropiophenone,20 g. of aluminum isopropoxide, and 200 ml. of dry isopropanol wasdistilled slowly for three hours. The isopropanol remaining in thereaction mixture was removed by distillation at reduced pressure. Theresulting brown pasty residue was warmed with 200 ml. of saturatedaqueous sodium chloride solution, and then filtered. The residualaluminum hydroxide on the filter was washed with several portions ofether. The ether layer was separated from the filtrate and dried overanhydrous calcium sulfate. The ether was then removed from the ethersolution by evaporation at reduced pressure. The dark amber oil obtainedas a residue was taken up in 100 ml. of hot benzene, filtered withcharcoal, and the filtrate was diluted with petroleum ether just shortof permanent turbidity. On standing, there separated from the solution 4g. of

. Y 17 solid which was recrystallized from benzene and then fromethylene chloride. The product thus obtained, which was2-dichloroacetylar1ino-1-(4-napropylmercaptophenyl)-l,3-propanediol,having the formula melted at 91.8-94.8 C.

E. LZ-DICHLOROACETYLAMINO-l- (4-n-PROPYLSULFON.YLPHENYL)-1,3-PROPANEDIOL 2 g. of2-dichloroacetylamino-l-(4-n-propylmercaptophenyl)-1,3-propanediol wasdissolved in 6 of acetone product, which was2-dichloroacetylamino-l-(4-nepropylsulfonylphenyl l ,3 -propanediol,weighed 1.2 g. and melted at 1829-1845 C.

EXAMPLE 7 .Z-dichloroacezfylamino-I- (4-n-butylsulf0nylv7zenyl)1,3-prpanedi0l onaom'onzonz-sor-cn-cn-omon ll which boiled at 138440 C.at 0.8 mm. and :melted at 24 25 C. after crystallization from petroleum:ether at 0 C. 110 g. of 4-n-butylmercaptoacetophenone dissolved in oneliter of chloroform was treated with .80 .g. of bromine to yield 168 g.of alpha-bromo-4-n-butylmercaptoacetoph'enone, havlng the formulaomomomom-s-Qgwom-m This compound was recrystallized from petroleumether, thus yielding large colorless crystals which melted :atapproximately 63" C. 60 g. of alpha-'bromo-4-n-butylmercaptoacetophenonedissolved in 300 ml. of acetonitr'ile was treated with 30 g. ofhexamethylenetetramine, thereby producing 88 g. ofalpha-bromo-4-n-butylmercaptoacetophenone-hexamethylenetetramine,adduct, having the formula which melted at approximately 113 C. withdecomposition. a

A mixture of 86 g. of .alpha-bromo-4-nbutylmercaptoacetophenonehexamethylenetetramine adduct, 85 .ml. ofconcentrated hydrochloric acid, and 170 ml. of ethanol was stirred forabout ten tours. The ammonium chloride which separated from the mixtureas a white solid was removed by filtration and discarded. The filtrate,after partial evaporation at room temperature .under reduced pressure,yielded 13.5 g. of a pale yellowish solid which melted at 140-145 C.(dec.). The filtrate from colleclion of this .solid was reduced involume by evaporation and a further yield of 35 g. of the product wasobtained as a brown gummy solid. This gummy solid was suspended in 50ml. of acetone, the solution was cooled in an ice-methanol bath, thesolid which separated from the cooled solution was collected on a filterand washed several times with cold acetone. There was thus obtained 26.5g. of a yellowish-tan solid which melted at l40145 C. (dec.). The twocrops of product melting at 140-145 C. were combined and the 40 g. ofproduct was recrystallized from ml. of water containing 3 m1. ofconcentrated hydrochloric acid. There was thus obtained 32.5 g. ofalpha-amino-4-nbutylmercaptoacetophenone hydrochloride having theformula in the form of white flaky crystals. A sample of this productwas recrystallized from ethanol and then again from water acidulatedwith hydrochloric acid to yield the pure compound which melted at175.5-179.3 C. (dec.).

B. A'LPHA-DICHLOROACETYLAMINWtm-BUTYLMER- CAPTOACETOPHENONE A mixture of27 g. of dry alpha-arnino-4-n-butylmercaptoacetophenone hydrochloride,125 ml. of anhydrous benzene, and 15 ml. of dichloroacetyl chloride wasstirred and heated for fifteen minutes reaction mixture was then cooledand the solid which separated from solution was collected on a filter.There was thus obtained 31.6 g. of alpha-dichloroacetylamino-4-n-butylmercaptoacetophenone having the formula.

ouromumom-mQo-on-omon which when recrystallized from benzene in the.form of small white crystals, melted at 123.0-123J8 C.

D. 2-DICHLOROACETYLAMINO-l-(4-n-BUTYLMERCAPTO- PHENYL)-1,3-PROPANEDIOLg. ofalpha-dichloroacetylamino-beta-hydroxy-4-nbutylmercaptopropiophenone,'65 g. of aluminum isopro poxide, and-one liter of dry isopropanol weredistilled slow benzene yielded melted at 127:4-128 C. with pressure, andthe reddish residue thus obtained was heated for thirty minutes with400ml. of water containing 40 g. of sodium chloride. The aluminumhydroxide which separated from solution was removed by filtration andthe filter cake was washed thoroughly with ether. The reddish etherlayer was separated from the filtrate, dried over anhydrous calciumsulfate, and the ether was re solution by evaporation under reducedpressure. The hght red viscous oily residue thus obtained was taken upin ml. of benzene, filtered with charcoal, and the filtrate was cooled.From the filtrate there separated 14 g. of '2-dichloroacetylainino1.(4-n- 19 butylmercaptophenyl) 1,3 propanediol, having the formulaonion.omomm-Qon-on-omon OH NH(1CHCh O which was recrystallized frombenzene and then from ethylene chloride to yield a white waxy solidwhich melted at 85.5-87.0 C. E.2-DICHLOROACETYLAMINO-i-(-4-n-BUTYLSULFONYL- PHENYL)-1,S-PROPANEDIOL 3.5g. of 2-dichloroacetylamino-1-(4-n-butylmercaptophenyl)-1,3-propanediolwas dissolved in 10 ml. of acetone and to this solution there was addedwith cooling 4 ml. of 40% peracetic acid. After stirring the reactionmixture for one hour, it was cooled to 10 C. The solid which separatedfrom the solution was collected on a filter. There was thus obtained 2.5g. of Z-dichloroacetylamino- 1-(4-n-butylsulfonylphenyl)-l,3-propanediolin the form of a pure white solid which melted at 131.6132.8 C. Anadditional 1.0 g. of this product was obtained by evaporation of thefiltrate.

EXAMPLE 8 Z-acetylamino-I-(4-benzylsulfonylphenyl) -1,3-

propanediol Gem-sm-Q-on-on-ornon 6H I IHC-CHs l! A.ALPHA-AMINO-4-BENZYLME'RCAPTOACETOPHENONE HYDROCHLORIDE 340 g. of benzylphenyl sulfide was dissolved in 1200 ml.-of anhydrous chloroform and 120ml. of acetyl chloride was added to the solution. The resulting mixturewas cooled to 10 C. and 226 g. of aluminum chloride was addedportionwise at such a rate that the temperature of the reaction mixturedid not exceed C. After the addition of the aluminum chloride wascompleted, the mixture was stirred and allowed to warm to 21 C. Themixture was then poured into ice water. The red chloroform layer wasseparated from the aqueous layer, washed with 300 ml. of dilutehydrochloric acid, and dried over anhydrous calcium sulfate. Thechloroform was then evaporated from the chloroform solution. There wasthus obtained as a residue 402 g. of a dark red oil. This oil wasdissolved in 1200 ml. of petroleum ether and the resulting solution wasfiltered hot with charcoal. The yellow filtrate was cooled in an icebath. 154 g. of yellow solid separated from the cooled solution. Thisproduct was recrystallized twice from ethanol and once from petroleumether. There was thus obtained, in the form of fine white needles whichmelted at 113.9115.3 C.

.4-henzylmercaptoacetophenone, having the formula 95 g. of4-benzylmercaptoacetophenone was dissolved in one liter of chloroformand was treated with 62.5 g. of bromine by a procedure similar to thebromination described above in Example 1A. To the solution of alphabromo4 benzylmercaptoacetophenone thus obtained there was added 5 6 g. ofhexamethylenetetramine and the mixture was stirred for two hours. Thepinkish-white solid which separated was collected on a filter and washedwith 200 ml. of chloroform. The resulting crude alpha-bromo-4-benzylrnercaptoacetophenone hexamethylenetetramine adduct, having theformula was hydrolyzed directly by stirring it for about ten hours atroom temperature (about 25 C.) with 180 ml. of concentratedhydrochloride and 360 ml. of ethanol. The reaction mixture was thencooled to 10 C. The solid was collected on a filter and dried. There wasthus ob tained 145 g. of crude reaction product. Ammonium chloride wasremoved from this product by slurrying it with 400 ml. of hot water forten minutes and then cooling the solution to 10 C. 67 g. of solidseparated from the cooled solution. This product was further purified byrecrystallization from water containing a little hydro: chloric acid.There was thus obtained alpha-arnino-4- benzylmercaptoacetophenonehydrochloride, having the formula in the form of white leaflets whichmelted at 2l4.5216.5 C. (dec.). 13.ALPHA-ACETYLAMINO-4-BENZYLMERCAPTOACETO- PHENONE To a slurry of 52 g. ofalpha-amino-4-benzylmercaptoacetophenone hydrochloride, 250 ml. of waterand 500 g. of ice there was added 40 ml. of acetic anhydride followed bythe immediate addition of a solution of 60 g. of sodium acetatetrihydrate in 250 ml. of water. The reaction mixture was stirred andallowed to warm to room temperature (about 25 C.), and was then madeacid to Congo by addition of hydrochloric acid. The solid was separatedfrom the mixture by filtration, washed with water, and dried. A smallsample of this product was purified by recrystallization from acetone.There was thus obtained alpha-acetylamino 4 benzylmercaptoacetophenone,having the formula in the form of white needles which melted atl62.6-l63.8 C.

C. ALPHA-ACETYLAMINO-BETA-HYUROXY- i-BENZYL- MERCAPTOPROPIOPHENONE Thecrude product from part B was slurried and warmed at 40 C. with 3.5liters of ethanol. To this mixture were added 45 ml. of formalin (37%aqueous solution of formaldehyde) and 4 g. of sodium bicarbonate.Stirring of the reaction mixture at 40 C. was continued for twenty-fourhours. The suspended sodium bicarbonate was removed from the solution byfiltration and the filtrate was evaporated to a volume of about ml.,diluted with water, and the white solid which separated from solutionwas collected on a filter. There was thus obtained 49 g. of pale yellowsolid. This product was recrystallized once from ethylene chloride andonce from nitroethane. There was thus obtainedalpha-acetylamino-beta-hydroxy- 4-benzylmercaptopropiophenone, havingthe formula 0 NliI-(fi-CH;

which melted at approximately 161 C.

D. Z-ACETYLAMINO-l- (4-BENZYLMERCAPTOPHENYL) 1,3-PROPANEDIOL A mixtureof 23 g. of alpha-acetylamino-beta-hydroxy-4-benzylmercaptopropiophenone, 30 g. of aluminum isopropoxide, and oneliter of dry isopropanol was refluxed for eighteen hours. During thistime isopropanol and acetone was allowed to distil slowly from thereaction mixture. The remaining isopropanol was then distilled ofi underreduced pressure and the dark red residue was heated for thirty minuteswith about 200 m1. of 5% aqueous sodium chloride solution on a steambath. The mixture was filtered and the residue thus collected was heatedwith 200 ml. of ethylene chloride. The mixture was 21 filtered hot toremove aluminum hydroxide, .and .thefiltrate was cooled. 11 g. of solidseparated from the cooled filtrate. This-solid was collected andpurified by recrystallization, first from nitroethane, then fromisopropanol, and finally, again from nitroethane. There was thusobtained, in the form of white leaflets which melted at l57..0158.0 C.,Z-acetylamino 1 :(4-benzylmercapto- ,phenyl) -.1,3-propanediol, havingthe formula H NH-G'O-Hx g E. 'Z-ACETYLAMINO-ll-BENZYLSIILFONYLPHE'NYL)'1,3-PIROPANEDI0L To a slurry of 0.6 g. of2-acetylamino-1-(4-benzylmercaptophenyl)-1,3-propanediol in'3 ml. ofacetone there was added at 20 C. 2 ml. of 40% peracetic acid in oneportion. The temperature of the mixture rose to 55 C. and the solutionbecame clear followedalmostimmediate- 1y by the separation of a solidproduct. The mixturewas stirred for an additional thirty minutes andthen cooled to C. The solid product was collected on afilter and washedwith three 2 ml. portions of acetone. There was thus obtained 0.6 g. ofWhite solid. of this solid from 70 ml. of nitroethane yielded smallwhite leaflets of 2-acetylamino 1 (4.benzylsulfonylphenyl)-1,3-propanediol which melted at 222.9223.'9 C.

EXAMPLE 9 2-dichloroacetylamin0-1-(4-benzylsulfonylphenyl) -1,3-propanediol This product, when purified by crystallization, first fromethylene chloride and then from nitroethane, melted at 185.6l86.4 C.

Proceeding in the manner set forth in the above examples,hydroxymethylation of thealpha-dichloroacetylamino-4-benzylmercaptoacetophenone by treatment withfonnaldehyde in the presence of an alkaline condensation catalyst yieldsalpha-dichloracetylamino-beta-hydroxy-4-benzylmercaptophenylacetophenone, having the formula 0 NH-C-OHCI:

Reduction of this compound with aluminum isopropoxide in isopropanolyields 2-dichloroacetylamino-l-(4-benzylmercaptophenyl)-1,3-propanediol. B. 2-DICHLOROACETYLAMINO-l-(A-BENZYLSULFONYL- PHENYL-l,3-PROPANEDIOL When, .for the 2acetylamino-l-(4-benzylmercaptophenyl)-1,3-propanediol employed as areactant in the oxidation procedure described in Example 8E, there issubstituted 2 dichloroacetylamin'o-1+(4benzylmercaptophenyl)-l,3-propanediol, there is obtained as the productallowed to "warm to room 1 3 -propanediol.

EXAMPLE l0 Z-dichlofoacetylamino-I-(4-phenylsulfortylphenyl)11,3-

propanediol 0 A. ALPHA-AMLVOA-PHENYLMERCAPTOACETOPHENONE HYDROCHLORIDE Amixture of .190 g. of diphenyl sulfide, .146 goof aluminum chloride, andone liter .of anhydrous chloroform was stirred and'cooled to '5 C. g. of.acetyl chloride was added to the mixture slowly, the temperature of themixture being kept .at 5 C. to +5 C. When an of the acetyl chloride had.beenadded, stirring was continued for one hour while the reactionmixture was gradually temperature. The mixture was then poured into icewater. The chloroform layer was separated from the mixture and thechloroform removed from the chloroform solution by distillation underreduced pressure. The residue thus obtained Was dissolved in a hotmixture of 150 ml. of benzene and 150 ml. of petroleum ether. When thesolution was cooled, 158 g. of 4-phenylmercaptoacetophenone, having theformula separated from solution. mately 66 C.

.A solution of 53 g. of 4 phenylmercaptoacetophenone in 50.0 ml.of-chloroform was treated with .36 g. ofbromine This product melted atapproxi- The 69 g. of oil was dissolved in 400 ml. of acetonitrile and32.6 g. of hexamethylenetetramine was added to the solution. The mixturewas stirred for thirty minutesand the white creamy solid was thencollected on a filter. There was thus obtained g. of crudealpha-bromo-4- phenylmercaptoacetophenone-hexamethylenetetramine ad-'duct, having-the formula s -nt s om nn (cumin which melted withdecomposition at approximately 206 C. This product was stirred andheated on .a steam bath for fifteen minutes with 250 ml.

by filtration and the filtrate was allowed to stand .for several hoursat room temperature. The white solid which separated from the solutionwas collected on a filter, dissolved in hot anhydrous ethanol, filteredhot with charcoal, and the filtrate was cooled. There separated from thecooled solution 22 g. of .alpha-amino-4-phenylmercaptoacetophenonehydrochloride, having the formula which melted at 216.7-217.0 C. (dec.).

B. ALPHA-DICHLOROACETYLAMINO-4-PHENYLMER- Y'CAPTOACETOPHEN ONE A mixtureof 22 g. of alpha-amino-4-phenylmercaptoacetophenone hydrochloride, 37g. of dichloroacetyl chloride, and 150 ml. of dry benzene was heatedunder reflux for thirty minutes. The hot reaction mixture was thenfiltered. 12 g. ofalpha-dichloroacetylamino-4-phenylmercaptoacetophenone separated fromthe filtrate on cooling. This product melted at 138.5l39.7 C. C.ALPHA-DICHLOROACETYLAMINO-BETA-HYDROXY-4 PHENYLMERCAPTOPROPIOPHENONE Amixture of 17 g. of alpha-dichloroacetylamino-4-phenylmercaptoacetophenone, 125 ml. of ethanol, ml. of formalin (37%aqueous solution of formaldehyde), and 1 g. of sodium bicarbonate wasstirred and heated at 40 C. for one hour and then allowed to stand forseveral hours at room temperature (about 25 C.). The reaction mixturewas then reheated to 40 C., filtered to remove sodium bicarbonate, andthe filtrate cooled. 11 g. of solid separated from the cooled filtrate.This product was recrystallized from ethylene chloride, thereby yielding10.5 g. of pure alpha-dichloroacetylamino-beta-hydroxy-4-phenylmercaptoacetophenone, having the formula l THC-GHCl2 ll whichmelted at 128.5129.5 C. D. Z-DICHLOROACETYLAMINO-l-(4 PHENYLMERCAPTO-PHENYL) -1,3-P\ROPANE"DIOL A mixture of 10 g. ofalpha-dichloroacetylamino-betahydroxy-4-phenylmercaptopropiophenone,20.4 g. of aluminum isopropoxide, and 100 ml. of dry isopropanol wasdistilled slowly for forty-five minutes. The excess isopropanol was thenremoved by distillation under reduced pressure and the residue washeated for thirty minutes with 100 ml. of 15% aqueous sodium chloridesolution. The aluminum hydroxide which separated from the mixture wascollected on a filter and washed thoroughly with ether. The aqueousfiltrate was also extracted with ether, and the ether washings andextracts were combined and dried over anhydrous calcium sulfate. Theether was then distilled from the filtrate under reduced pressure. Therewas thus obtained as a residue 5.0 g. of 2-dichloroacetylamino-1-(4-phenylmercaptophenyl)-1,3-propanediol, having the formula in the formof a red oil.

E. Z-DICHLOROACETYLAMINO-( i-PHENYLSULFONYL- PHENYL) -1,3-PROPANEDIOLOxidation of theZ-dichloroacetylamino-l-(4-phenylmercaptophenyl)-l,3-propanediol withperacetic acid in a manner similar to the oxidizing procedures describedin the foregoing examples yields 2-dichloroacetylamino-1-(4-phenylsulfonylphenyl) 1,3 -prop anediol.

Proceeding in accordance with the teachings of the above examples, therecan be prepared the following compounds:

2 iodoacetyl-l-[4-(p-tolylsulfonyDphenyl] 1,3 propanediol, by oxidizing2-iodoacetyl-1-[4-(p-tolylrnercapto)phenyl] -l,3-propanediol, which isprepared by hydroxymethylating alpha-iodoacetylamino-4-(p-tolylmercapto) acetophenone and reducing thealpha-iodoacetylaminobeta-hydroxy-4-(p-tolylmercapto)propiophenone thusobtained;

2 beta chloropropionylamino l (4 cyclohexylsulfonylphenyl) 1,3propanediol, by oxidizing 2 betachloropropionylamino 1 (4cyclohexyhnercaptophenyl)-1,3-propanediol, which is prepared byhydroxymethylating alpha (beta chloropropionylamino 4cyclohexylmercaptoacetophenone and reducing thealpha-(betachloropropionylamino) beta -hydroxy 4 cyclohexyl'mercaptopropiophenone thus obtained,

2 acetylamino 1 (4 methallylsulfonylphenyl) 1,3- propanediol, byoxidizing 2 acetylamino 1 (4 methallylmercaptophenyl)-1,3-propanediol,which is prepared by hydroxymethylating alpha acetylamino 4methallylmercaptoacetophenone and reducing the alpha acetylamino betahydroxy 4 methallylmercaptopropiophenone thus obtained;

2 trilluoroacetylamino 1 (4 methallylsulfonylphenyl) 1,3 propanediol, byoxidizing 2 trifluoroacetylamino 1 (4 methallylmercaptophenyl) 1,3propanediol, which is prepared by interacting ethyl trifluoroacetate and2 amino 1 (4 methallylmercaptophenyl)- 1,3-propanediol obtained bydeacylating the corresponding 2-acetylamino compound;

2 (alpha methylpropionylamino) 1 (4 isobutylsulfonylphenyl) 1,3propanediol, by oxidizing 2 alphamethylpropionylamino) 1 (4isobutylmercaptophenyl)1,3-propanediol, which is prepared by interacting2- amino 1 (4 isobutylmercaptophenyl) 1,3 propanediol withalpha-methylpropionyl chloride; and

2 (alpha,beta dichloropropionylamino) l (4 tert.- butylsulfonylphenyl)1,3 propanediol, by oxidizing 2- (alpha,beta dichloropropionylamino) 1(4 tert. butylmercaptophenyl) 1,3 propanediol, which is prepared byhydroxymethylating alpha (alpha,beta dichloropropionylamino) 4 tert.butylmercaptoacetophenone and reducing the alpha (alpha,betadichloropropionylamino) beta hydroxy 4 tert. butylmercaptopropiophenonethus obtained.

The racemic and the dextro-rotary forms of the 2- aliphatic carboxylicacylamino 1 (4 hydrocarbylsulfonylphenyl) 1,3 propanediols (l) of myinvention have been found to have especially high antibiotic activity,being active against gram-negative and gram-positive bacteria andrickettsial organisms. In general, the dextrorotary form is more activethan the racemic form. In many instances, the dextro-rotary form hasapproximately twice the antibacterial activity of the racemic form.

I claim:

1. A 2 lower aliphatic carboxylic acylamino 1 (4-hydrocarbylsulfonylphenyl) 1,3 propanediol having the formulan-sm-Qon-on-omon OHY where R is a hydrocarbyl radical having 1-7 carbonatoms and Y is a lower aliphatic carboxylic acylamino radical. 2. A halolower alkanoylamino 1 (4 hydrocarbylsulfonylphenyl) 1,3 propanediolhaving the formula where R is a hydrocarbyl radical having 17 carbonatoms.

3. A 2 halo lower alkanoylamino 1 (4 alkylsulfonylphenyl) 1,3propanediol having the formula where R is an alkyl radical having l-7carbon atoms.

4. A 2 dichloroacetylamino 1 (4 alkylsulfonylphenyl) 1,3 propanediolhaving the formula where R is an alkyl radical having 1-7 carbon atoms.

25 5. A 2 amino 1 (4 hydrocarbylsulfonylphenyl)- 1,3 propanediol havingthe formula OH NH:

where R is a hydrocarbyl radical having 1-7 carbon atoms. 6. A 2 amino 1(4 alkylsulfonylphenyl) 1,3- propanediol having the formula where R isan alkyl radical having 17 carbon atoms.

7. A compound of the formula 15 RS oOgrr-om-omon wherein R is a memberof the group consisting of methyl, ethyl and phenyl.

8. The compound 1 (para-methy1sulfonylphenyl) 2 amino 1,3 propanediol.

9. A compound of the formula NH-COCHCI:

No references cited.

1. A 2 - LOWER ALIPHATIC CARBOXYLIC ACYLAMINO - 1 -(4HYDROCARBYLSULFONYLPHENYL) - 1,3 - PROPANEDIOL HAVING THE FORMULA